Oral squamous-cell carcinoma (OSCC) is classified as a head and neck cancer and is a tumor that is mainly generated from oral mucous membrane epithelia and the like. Among head and neck cancers, OSCC incidence is as high as about 35% and has some influences on 270,000 people worldwide every year (Parkin, D. M., et al., CA Cancer J Clin. 55, 74-108, 2002). The most common site of the origin of oral squamous-cell carcinoma is tongue, and the second most common site thereof is gingiva (gum). Oral squamous-cell carcinoma is known to be developed at other mucous membranes of the oral cavity, such as buccal mucosa, palate, and mouth floor. Furthermore, oral squamous-cell carcinoma is also known to be developed at jaw bone or salivary gland.
In recent years, although procedures for diagnosis and treatment for oral squamous-cell carcinoma have been advanced, the prognosis thereof has remained unimproved. Accordingly, it has been desired to discover a causative gene for oral squamous-cell carcinoma and to elucidate the functions for establishment of new strategic understandings for effective therapeutic methods and chemical prevention.
It has been known from long ago that the onset of cancer is caused by mutation in the proteins of cells or a quantitative change thereof. The recent development of genetic engineering has enabled amplification of genes encoding specific proteins and the analyses of gene mutations in cancer cells, and it has brought on significant progression in the field of cancer researches. To date, the analysis and identification of what are called “oncogene” associated with malignant transformation of cells or abnormal proliferation of cancer cells have been proceeded. On the other hand, antioncogenes, whose mutation or decrease in expression would lead to malignant transformation, have come under the spotlight in recent years. As such antioncogenes, an Rb gene of retinoblastoma, a p53 gene and an APC gene of colon cancer, a WT1 gene of Wilms' tumor, and so on have been discovered so far. A case of a cancer-suppressing agent that utilizes the WT1 gene has also been reported (WO2003/002142).
Moreover, it has been gradually revealed that the abnormity of, not only a single gene, but also multiple genes, is involved in the onset, malignant transformation and metastasis of cancer, etc. It has been considered that there would be more unidentified oncogenes and antioncogenes. A large number of genes having an effect of suppressing cancer have been known. In order to select such antioncogenes, an approach for finding such genes by staining chromosomal DNA to visualize the gene mutation of a patient (Yasuhide Yamashita, et al., World J Gastroenterol, 11(33): 5129-5135, 2005) and a method comprising roughly selecting a gene deletion by an LOH (Loss of Heterozygosity) analysis and narrowing down an important gene region (WO01/032859) have been applied in many cases. However, these methods have been disadvantageous in that a DNA deletion region to be detected would be large and in that large amounts of time and labor would be required for an operation to narrow down an important gene region. Thus, these methods have had certain limits as means for finding out antioncogenes. Furthermore, it has been difficult to determine the degree of malignancy by conventional methods for separating and differentiating the pathologic condition of cancer.
In order to solve the aforementioned problems, the present inventors have discovered novel antioncogenes such as a CDKN2A gene, a CDH1 gene, an MGMT gene, an RARB gene, an RASSF1A gene, a DAPK gene, an MLH1 gene and an LRP1B gene, and they have reported such genes (Nakagawa T, Pimkhaokham A, Suzuki E, Omura K, Inazawa J, Imoto I., Genetic or epigenetic silencing of low density lipoprotein receptor-related protein 1B expression in oral squamous cell carcinoma. Cancer Sci 2006; 97: 1070-4). Further, it has also been reported that an FAT gene functions as an antioncogene and that the homozygous deletion of the FAT gene may cause the tumorigenic transformation of oral cavity cancer (Nakaya K, Yamagata H. D., Arita N, et al., Identification of homozygous deletions of tumor suppressor gene FAT in oral cancer using CGH-array. Oncogene 2007; 26: 5300-8). However, in order to analyze the mechanism of a cause of cancer at a genetic level and utilize it in diagnoses, it has been necessary to analyze more gene mutations.